DD148055A5 - PROCESS FOR PREPARING O-SUBSTITUTED DERIVATIVES OF (+) - CYANIDAN-3-OLS - Google Patents

Abstract

Process for the preparation of derivatives of the (+) - cyanidan-3-ol of the formula I, in which R 1 ind is a protected oxy group which is readily hydrolyzable or hydrogenolysable, characterized in that (+) - cyanidan-3 in an aprotic and organic solvent having a high dielectric constant, treated with an alkali metal hydride or alkali metal carbonate, and the resulting tetra-alkaline salt with a reactive ester of the formula HOR & ind1! The ratio of cyanidan-3-ol, alkali hydride and reactive ester 1: about 4.25: about 4.5, and the ratio cyanidan-3-ol, alkylic carbonate and reactive ester 1: about 8: about 6 accounts. These compounds are intermediates e.g. for the preparation of the pharmacologically valuable compounds described in patent application APC07D / 209343 (Case 4-11475 / ZYM 26/1 + 2 / +).

Description

AP C 07 D / 217 791 56 655 12

Process for the preparation of o-substituted derivatives of (+) - cyanidan-3-ol

Field of application of the invention

The invention relates to production process of o-substituted derivatives of (+) - cyanidane-3 ~ -ol _? as intermediates for the preparation of compounds of the formula

OH

can be used. The end compounds are pharmacologically active.

Well-known technical solutions

It is known that (-t -) - cyanidan-3-ol has a liver protection effect. Other activities have not been observed so far.

Object of the invention

It is an object of the invention to provide intermediates for novel pharmacologically active compounds.

Essence, the invention

The invention has for its object to provide a process for the preparation of derivatives of (-O-cyanidan-3-ol of the formula I.

217791

AP C 07 D / 217 791 56 655 12

According to the invention, O-substituted derivatives of (+) - cyanidan-3-ol, in particular those of the formula I, are prepared

(D

wherein R.O. represents a protected oxy group which is readily hydrolyzable or hydrogenolyzable.

The new compounds are intermediates for the preparation of the end products mentioned above. The end products in particular have an interesting activity in preventing hepatic fecrosis and prevent lipoperoxidation. They can also prevent the breakdown of collagen, as well as the effectiveness of lysosomal enzymes by increasing the stability of lysosomal membranes. They can also affect permeability and vascular tone.

In the compounds of the formula I, the radical R may be a lower alkyl radical which is mono-, di- or polysubstituted, a lower alkenyl radical, an unsubstituted or mono-, di- or trisubstituted araliphatic radical, an aliphatic, aromatic or araliphatic carboxylic acid radical or an esterified radical Carbonic acid residue, or a radical which forms a cyclic acetal with the oxygen atom bound to R.

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When R 1 represents a lower alkyl radical, it preferably contains 1-4 carbon atoms and is primarily methyl or ethyl. These residues can be replaced by lower alkoxy, e.g. Ethoxy or methoxy, or lower alkoxyethoxy, e.g. Methoxyäthoxy be substituted.

If R. is a lower alkenyl radical, this preferably contains 2-5 carbon atoms and is primarily allyl / methallyl, 2-butenyl or 2-pentenyl.

When R, is an araliphatic, especially a benzyl radical, it may be variously substituted, e.g. by 1 or more alkyl having 1-4 carbon atoms, such as methyl, ethyl, isopropyl or tert-propyl, by one or more halogens preferably chlorine, bromine or fluorine, one or more alkoxy, such as methoxy or ethoxy or else by nitrile. These substituents can occupy the ortho and para positions; they are preferably in the para position. If a substituent in the radical R, of the second order, such as the nitro group, it is preferably in the meta position.

When the radical R is an aliphatic acyl radical, the aliphatic part is e.g. an alkyl of 1-4 carbon atoms, and preferably methyl or ethyl, which may be substituted by lower alkoxy such as methoxy. When R. is an aromatic or araliphatic acyl radical, the aromatic radical is especially a phenyl radical which is optionally substituted, and the aliphatic radical is an alkyl having 1-2 carbon atoms.

When R is an alkoxycarbonyl, the alkyl radical may again be substituted by an aryl or by a halogen atom. If R is an acetal together with the oxygen which carries the radical R, this acetal can be linear or cyclic, for example a pyranyl radical.

Particular mention may be made of the radicals of the formula R ₁ , for example allyl, methallyl, ethylallyl, 2-butenyl, 2-pentenyl, methoxymethyl, ethoxymethyl, methoxyethoxymethyl, acetonyl, propionylmethyl, cinnamyl, phenacyl, benzyl,

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2-methylbenzyl, 4-methylbenzyl, 4-t-butylbenzyl, 4-bromobenzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-methoxybenzyl, 4-ethoxybenzyl, '3-nitrobenzyl, 3,5-dinitrobenzyl, 4-cyanobenzyl , Chloro, bromo ^ or phenyl-phenacyl or methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, or phenoxycarbonyl.

The compounds containing a salt-forming group, such as carboxyl groups, can be obtained in free form or in the form of their salts. These forms can be mutually converted one into the other. Salts of compounds containing a free carboxylic acid are e.g. Metal salts, especially alkali metal salts e.g. Sodium or potassium salts, as well as alkaline earth metal salts, e.g. Gastric or calcium salts, or ammonium salts e.g. with ammonia or organic bases, such as tri-lower alkylamine, e.g. Trimethylamine or triethylamine. These salts are obtained, e.g. by reacting the free compound with hydroxides or carbonates of these metals or with ammonia or amines, or else with suitable ion exchangers, or with organometallic compounds.

Compounds having basic groups may also be present in the form of their acid addition salts, especially non-toxic pharmaceutically acceptable acids, e.g. with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, or with organic carbon or sulfonic acids e.g. aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic acids, e.g. Acetic, propionic, succinic, gliconic, lactic, maleic, tartaric, citric, ascorbic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, aminosalicylic, embonic or nicotinic acids, as well as methanesulfonic

acid, ethylenesulfonic acid, phenylsulfonic acid, p-methylphenylsulfonic acid, naphthalenesulfonic acid, sulfanylic acid, or cyclohexylsulfamic acid. These salts may e.g. by treating the free compounds containing a basic group with said acids or corresponding anion exchangers.

The new compounds containing basic groups may also be incorporated into their quaternary ammonium salts e.g. by treatment with alkylating agents such as lower alkyl halides e.g. Iodomethyl, lower alkyl or benzyl sulfates such as methyl sulfate.

The compounds of formula I are intermediates e.g. for the preparation of the compounds described in the patent application AP C O7 / D / 2O9 343, (Case 4-11475 / ZYM 26/1 + 2 / +). They are known in part, but new to a greater extent. They can be obtained according to a known method or especially by a new and advantageous manner. So you can, for example (+) - Cyanidan-3-ol or one of its salts with a reactive ester of an alcohol of the formula

HO-R in which R has the abovementioned meaning, implement.

A reactive ester is especially an ester with a strong inorganic acid, primarily a hydrohalic acid such as hydrochloric or hydrobromic or an organic sulfonic acid, preferably a lower alkanesulfonic acid e.g. Methane or ethanesulfonic acid or a benzenesulfonic acid which in the benzene nucleus e.g. may be substituted by methyl, chlorine or bromine, such as p-toluene sulfonic acid or p-bromobenzenesulfonic acid.

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By this method one obtains derivatives of (+) -cyanidan3-ol whose 4-phenolic hydroxy groups are substituted. Among these tetraethers, 5,7,3 ', 4'-tetra-O-benzyl - (+) - cyanidan-3-ol has already been prepared by a pure laboratory method. [K. Weinges et D. Seiler, Liebigs Ann. Chem. JI 193-204 (1968)]. In this reaction, (+) - cyanidan-3-ol dissolved in acetone was reacted with benzyl chloride in the presence of potassium iodide and potassium carbonate under nitrogen and refluxed for several hours. It is a classical benzylation and, after separation and crystallization from ethanol, results in a mixture of 8-benzyl-5,7,3 ', 4'-tetra-O-benzyl - (+) - cyanidan-3-ol and 5,7,3 ', 4'-tetra-O-benzyl - {+) - cyanidan-3-ol. The latter is isolated by chromatography in 1-2% yield. This yield is so small that this method for the production of tetrasubstituierten compounds can not be used industrially.

It has now been found that these compounds can be obtained in very good yield by treating (+) - cyanidan-3-ol in an aprotic and organic solvent with high dielectric constant with an alkali metal hydride or alkali metal carbonate and the resulting tetraalkali salt with a reactive ester the formula

wherein the ratio of cyanidan-3-ol, alkali hydride and reactive ester is 1: about 4.25: about 4.5 or the ratio of cyanidan-3-ol, alkali carbonate and reactive ester 1: about 8: about 6.

-ISi-

The alkali hydride is especially sodium hydride and is preferably used in the form of a dispersion in OeI. The alkali carbonate is especially potassium carbonate.

The aprotic solvents used are especially amides, such as dimethylformamide, but also sulfoxides, such as dimethyl sulfoxide. However, dimethylformamide is preferred for economic reasons because it can be recovered by simple distillation at normal pressure, and because it is easier to handle than dimethylsulfoxide.

Moreover, it is important that the reaction milieu is as dry as possible. Thus, the dimethylformamide is dried over a molecular sieve and the solution of cyanidanol in dimethylformamide is dried in the same way. The formation of by-products is thereby avoided, without the drying of the formation of the desired products preclude.

The reaction may be carried out in the presence of a quaternary ammonium salt such as tetra-n-butylammonium hydrogensulfate, used in a proportion of 0.1 to 0.5 moles per 1 mole of cyanide-ol, or of a crown ether, preferably 18-crown-6 is used in an amount of 0.5 mole per 1 mole of cyanide-ol.

The reaction is carried out at a temperature between -25 ° C and about +50 ⁰ C. Since it is known that the dimethylformamide begins to decompose already at room temperature in contact with basic substances, this reaction is preferably carried out at -25 ⁰ C to + 25 ⁰ C and primarily at about -5 ⁰ C to about O ⁰ C through. With dimethyl sulfoxide, since it hardly decomposes, the reaction can be carried out at a temperature lower than 50 ° C, preferably between +15 ⁰ C and about +30 ⁰ C eg at room temperature.

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Since the alkali salt of (+) - cyanidan-3-ol in dimethylformamide-sodium hydride is not stable even at low temperature, the esterification or etherification agent must be added immediately. If this is not done, the reaction yield is reduced and the purification phase of the desired product is difficult. After the addition of the etherifying agent at low temperature, it is maintained for a while before slowly raising the temperature, e.g. to room temperature. The reaction is then completed and the reaction mixture can be stored in this state for more than 15 hours without changing the quality of the desired product. Good stirring is necessary during the reaction.

The progress of the reaction can be monitored by thin layer chromatography on silica gel using chloroform or dichloromethane as the mobile phase.

After the solvent has been removed from the reaction medium by distillation, the residue is taken up in an aprotic solvent. Trichlorethylene is particularly suitable as a solvent for the crystallization of the desired product. Other solvents such as carbon tetrachloride, toluene, ethyl acetate, ethanol, isopropanol or mixtures of these solvents e.g. with carbon tetrachloride, η-hexane, or acetone-methanol, give good results. Ethylene ether and η-hexane as well as acetone, pyridine, chloroform, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran and dichloromethane are less suitable because the new substances are soluble therein at room temperature.

The following examples illustrate the invention described above; however, they are not intended to limit their scope in any way. Temperatures are given in Celsius degrees.

example 1

0.96 g of a 55% dispersion of sodium hydride in OeI are added to a 50 ml flask with a feed nozzle, a nitrogen feed and a condenser carrying a calcium chloride tube, and the whole is dried by heating in a stream of nitrogen. After cooling under a gentle stream of nitrogen, 10 ml of freshly distilled dimethyl sulfoxide are added and the mixture is stirred at room temperature. A solution of 1.45 g of (+) - cyanidan-3-ol in 15 ml of freshly distilled dimethyl sulfoxide is added dropwise, during which hydrogen is evolved. 30 minutes later, a solution of 2.74 ml Methoxyäthoxymethylchlorid in 10 ml of dimethyl sulfoxide and poured 30 minutes later, the reaction solution in 150 ml of saline-saturated water, and pH adjusted to 7. A sticky brown-black precipitate is obtained with 3 times 100 ml of toluene extracted. The resulting solutions are combined and washed 3 times with 50 ml of water. The toluene is removed and the obtained brown-red OeI is extracted 10 times with 100 ml of η-hexane at reflux. The n-hexane solutions give the 5,7,3 ', 4'-tetra-O-methoxyethoxymethyl - (+) - cyanidan-3-ol as a yellow oil, which decomposes at 15O ° C / O, O2 mmHg becomes.

Example 2

Under nitrogen and with good stirring, a suspension of 92.8 g of a 55% dispersion of sodium hydride in OeI (51 g NaH) in one liter of freshly distilled dimethylformamide is prepared. It is cooled to a temperature between -5 and ^{0 0} C and to a solution of 145 g of (+) - cyanidan-3-ol in 2 liters of freshly distilled dimethylformamide to, so that the dispersion temperature remains constant. Hydrogen is removed by circulating nitrogen.

_o 217791

After introduction of (+) - cyanidan-3-ol, the mixture is allowed to stand at low temperature for 15 minutes, then 267.5 ml of benzyl bromide are added over 1½ hours, so that the temperature does not rise above ⁰ ° C. , It is allowed to stand at this temperature for half an hour and then warmed to room temperature.

The dimethylformamide is distilled off in vacuo at 60 ^° C., the oily residue is taken up in 3 liters of trichlorethylene, the organic solution is washed with 3 liters of distilled water and filtered. It is concentrated and cooled to give 5,7,3 ', 4'-tetra-O-benzyl - (+) - cyanidan-3-ol, which crystallizes in white needles. F = 144-145 ° C.

Example 3

Under the same conditions as in Example 2, but using dimethylformamide which has been thoroughly dried, the 5,7,3 ', 4'-tetra-O-benzyl - (+) - cyanidan-3-ol is obtained. Yield 55%

Example 4

Analogously to Example 2, but using 2.25 mol of benzyl chloride, the tetra-O-benzyl-5,7,3 ', 4' - (+) - cyanidan-3-ol. Yield 57%

Example 5

To a solution of 0.93 g of sodium hydride dispersion in OeI (0.51 g NaH) in 10 ml dimethyl sulfoxide which was freshly distilled, slowly added with stirring and at room temperature a solution of 1.45 g (+) - cyanide 3-ol in 20 ml of freshly distilled dimethyl sulfoxide. The resulting hydrogen is removed by circulating nitrogen. After stirring for one hour at room temperature, nitrogen evolution virtually ceases and the sodium salt of the (+) - cyanidan-3-ol is partly at the bulb wall

deposited. Then 2.68 ml of benzyl bromide are added dropwise. The mixture is allowed to stand for 1 1/2 hours with stirring at room temperature, the reaction solution is slowly and with stirring in 300 ml of a cold aqueous, 10% solution of sodium chloride. The precipitate is filtered off, and dried in vacuo at 80 ⁰ C, then recrystallized from 40 ml of carbon tetrachloride. This gives 1.96 g of 5,7,3 ', 4'-tetra-O-benzyl - (+) - cyanidan-3-ol.

Example 6

The procedure is as in Example 2, but using 416 g of α-bromo-o-xylene instead of benzyl bromide. The residue obtained after evaporation of the dimethylformamide is taken up in chloroform, the solution washed with distilled water, filtered and evaporated. The residue is crystallized from a mixture of benzene and petroleum ether (6: 3 v / v). This gives the 5,7,3 ', 4'-tetra-O- (2-methyl-benzyl) - (+) - cyanidan-3-ol of F 88-9O ° C. Yield 51%

Example 7

Analogously to Example 2, but using 416 g of a-bromop-xylene instead of benzyl bromide, the 5,7,3 ', 4'-tetra-O- (4-methyl-benzyl) - (+) - cyanidane-3 -ol which melts after recrystallization from carbon tetrachloride at 66-7O ⁰ C. Yield 40%

Example 8

Analogously to Example 2, but using 562 g of 2-bromobenzyl bromide instead of benzyl bromide gives the 5,7,3 ', 4'-tetra-O- (2-bromo-benzyl) - (+) - cyanidan-3-ol , which is recrystallized from a mixture of chloroform and carbon tetrachloride (40:55 v / v). F = 155-157 ° C. Yield 74%

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Example 9

Analogously to Example 2, but using 181 g of chlorodimethyl ether instead of benzyl bromide gives the 5 / 7,3 ', 4'-tetra-O-methoxymethyl - (+) - cyanidan-3-ol, which after recrystallization from a mixture of Water with methanol (1: 1 v / v) at 92-93 ° C melts. Yield 40%

Example 10

Analogously to Example 2, but using 272 g of allyl bromide instead of benzyl bromide to get the 5,7,3 ', 4' · tetra-0-allyl - (+) - cyanidan-3-ol after recrystallization from η-hexane at 78.5-8O ° C melts.

Example 11

Analogously to Example 2, but using 244 g of ethyl chloroformate instead of benzyl bromide gives the 5,7,3 ', 4'-tetra-O-ethoxycarbonyl - (+) - cyanidan-3-ol whose melting point is approximately at 65 ° C. , Yield 52%

Example J.2

Dissolve 1.45 g of (+) - cyanidan-3-ol in 50 ml of anhydrous acetone, add 6.91 g of anhydrous potassium carbonate and heat it at reflux in nitrogen. To this solution is added a solution of 6.26 g of p-bromo-phenacyl bromide in 30 ml of anhydrous acetone and allowed to continue to boil with mechanical stirring for 3 hours. After cooling the reaction mixture, the salts are filtered off and the solution is evaporated to dryness. The residue is taken up in 50 ml of chloroform, the chloroform solution is washed 3 times with 50 ml of water, the chloroform is evaporated off, the residue is dissolved

_ _u _ 21 779 f

in about 1000 ml of ether, filtered and concentrated the ethereal solution to 150 ml. This gives the 5,7,3 ·, 4'-tetra-O- (4-bromo-phenacyl) - (+) - cyanidan-3-ol, which after recrystallization to ethanol at 127-129 ⁰ C sqhmmzt. Yield 53.8%

Example 13

110 g of potassium carbonate in a 1 liter flask under weak nitrogen, then 250 ml of dimethylformamide, and poured into a solution of 29.0 g of (+) - cyanidan-3-ol in 250 ml of dried dimethylformamide and 71.25 ml of benzyl bromide dissolved in 100 ml of dimethylformamide. The mixture is heated to 100 ^° C. for 5 1/2 hours with stirring and in a stream of nitrogen. Die.erhaltene suspension is filtered hot, the filtrate was evaporated at 80 ⁰ C in a vacuum on a rotary evaporator and the residue dissolved with 250 ml of chloroform. The chloroform solution is filtered, washed 3 times with 250 ml of water, dried over magnesium sulfate and evaporated to dryness. The residue is taken up in 750 ml of refluxing carbon tetrachloride, the brown sticky residue is separated and allowed to crystallize at room temperature with stirring and occasional cooling in a refrigerator. The product obtained is identical to that of Example 2. F = 144-145 ° C.

Example 14

A 500 ml flask is equipped with a mechanical stirrer, an infuser, a calcium chloride tube and a supply of nitrogen. The whole is dried and placed under nitrogen before adding 100 ml of anhydrous dimethylformamide. It is cooled to -3 ⁰ C, 9.28 g of an oily dispersion of sodium hydride (55%) and then with vigorous stirring, a solution of 14.5 g (+) - cyanide

_ ₁₄ _ 217791

3-ol in 200 ml of anhydrous dimethylformamide, 1.698 g of tetra-n-butylammoniumhydrogensulfat and kept under stirring for 1 hour at ^{0 0} C. Then, within 15 minutes, a solution of 25.9 ml of benzyl chloride in 25 ml of anhydrous dimethylformamide and stirred during 30 minutes at ⁰ ° C. The temperature is allowed to rise to room temperature, the reaction mixture is kept under vigorous stirring for 24 hours, filtered and concentrated by evaporation under reduced pressure. The residue is taken up in 250 ml of chloroform, the solution washed 4 times with 250 ml of distilled water, dried over magnesium sulfate, filtered and evaporated. The residue is washed with 50 ml of hexane and then brought to constant weight. This mass is dissolved hot in 500 ml of carbon tetrachloride, filtered hot and cooled by cooling to room temperature and then concentrated to 350 ml and 150 ml of the 5,7,3 ·, 4'-tetra-O-benzyl - (+) - cyanidane-3 -ol which is identical to the product obtained in Example 2.

Example 15 .

As in Example 13, after the introduction of the cyanidanol solution, 13.22 g of 18-crown-6 are added and the benzyl bromide is replaced by 69 ml of benzyl chloride. The mixture is then heated for 20 hours with vigorous stirring at 60 ⁰ C. This gives the 5,7,3 '^' - tetra-O-benzyl - (+) - cyanidan-3-ol that obtained with the product obtained in Example 2 is identical.

Example 16

The procedure is analogous to Example 15, but replaces the 18-crown-6 by 16.98 g of tetra-n-butylammonium hydrogen sulfate. This gives 44.5 g of 5,7,3 ·, 4'-tetra-O-benzyl - (+) - cyanidan-3-ol.

Claims (1)

Claim 1. . Process for the preparation of derivatives of (+) cyanidan-3-ol of the formula I. (I) OH R ₁ O in which RO is a protected oxy group which is readily hydrolyzable or hydrogenolyzable, characterized by treating (+) cyanidan-3-ol in a high dielectric constant aprotic and organic solvent, with an alkali hydride or alkali carbonate, and the resulting tetra-alkali salt with a reactive ester of the formula HOR ₁ , wherein the ratio cyanidan-3-ol, alkali hydride and reactive ester 1: about 4.25: about 4.5, or the ratio cyanidane-3-ol, alkylicarbonate and reactive ester 1 : about 8: about 6.